1. Field of the Invention
The present invention relates to novel compounds having the structural formula I: ##STR2## in which n is 0, 1 or 2, ##STR3## is Boc-L-Phe; or a Boc-L-Phe surrogate such as ##STR4## in which W is (C.sub.1 -C.sub.4 alkyl).sub.3 C-- or (C.sub.1 -C.sub.4 alkyl).sub.2 CH--; R.sup.2 is alkyl; and Y is OR.sup.3 or NR.sup.4 R.sup.5 in which R.sup.3 is hydrogen or alkyl and R.sup.4 and R.sup.5 are independently hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, N-substituted aminoalkyl, N-substituted carbamoylalkyl, or R.sup.4 and R.sup.5 taken toqether with the nitrogen forming a 5 or 6 membered saturated or unsaturated ring.
These compounds exhibit renin inhibitory activity and are thus useful in the treatment of renin-associated hypertension and hyperaldosteronism.
The present invention is also concerned with pharmaceutical compositions containing the novel compounds of the present invention as active ingredients, with methods of treating renin-associated hypertension and hyperaldosteronism, with diagnostic methods which utilize the novel compounds of the present invention as well as methods of preparing the novel compounds of the present invention.
Renin is a proteolytic enzyme of molecular weight about 40,000, produced and secreted by the kidney. It is secreted by the juxtaglomerular cells and acts on the plasma substrate, angiotensinogen, to split off the decapeptide angiotensin I, which is converted to the potent pressor agent angiotensin II. Thus, the renin-angiotensin system plays an important role in normal cardiovascular homeostasis and in some forms of hypertension.
In the past, attempts to modulate or mainpulate renin-angiotensin system have met with success in the use of inhibitors of angiotensin I converting enzyme. In view of this success, it seems reasonable to conclude that a specific inhibitor of the limiting enzymatic step that ultimately regulates, angiotensin II production, the action of renin on its substrate, would be at least equally successful. Thus, an effective inhibitor of renin has been long sought as both a therapeutic agent and as an investigative tool.
2. Brief Description of the Prior Art
Renin inhibitors having the structural formula such as II, in which n=0 or 1, ##STR5## are known. See for example U.S. Pat. No. 4,650,661, EP 155,809, and EP 163,327. EP 236,734 discloses renin inhibitors in which "Boc Phe" is replaced by a surrogate containing a t-butyl sulfone group.
U.S. Pat. No. 4,609,641 discloses compounds of the type: ##STR6## in which "X"=OR' or NR"R'" and R=H, alkyl etc. EP 172,347 discloses compounds of the type: ##STR7## wherein n=0, 1, or 2 and R is alkyl, cycloalkyl, aryl or aralkyl. EP 184,855 discloses compounds of the type: ##STR8## However, none of these references describe or suggest renin inhibitory compounds containing the moiety 2-[[(2R,3S)-3-amino-4-cyclohexyl-2-hydroxy-1-butyl]thio]alkanoyl and the sulfoxide and sulfone thereof of the formula VII. ##STR9## It is the presence of this moiety in the instant Compounds I which distinguishes over the prior art compounds described above.
For other articles describing previous efforts to devise renin inhibitors, see Marshall, Federation Proc. 35: 2494-2501, 1976; Burton et al., Proc. Natl. Acad. Sci. USA 77: 5476-5479, September 1980; Suketa et al., Biochemistry 14: 3188, 1975; Swales, Pharmacol. Ther. 7: 173-201, 1979; Kokubu et al., J. Antibiotics 28: 1016-1018, December 1975; Lazar et al., Biochem. Pharmacol. 23: 2776-2778, 1974; Miller et al., Biochem. Pharmacol. 21: 2941-2944, 1972; Haber, Clinical Science 59: 7s-19S, 1980; Rich et al., J. Org. Chem. 43: 3624, 1978, and J. Med. Chem. 23: 27, 1980; Burton et al., U.S. Pat. No. 4,269,827; Castro et al., U.S. Pat. No. 4,185,096; and Sankyo Jap. Pat. No. 76-067001.